Randomized multicenter follow-up trial on the effect of radiotherapy on painful heel spur (plantar fasciitis) comparing two fractionation schedules with uniform total dose: first results after three months’ follow-up

The painful heel spur or plantar fasciitis was first described by Plettner [1] summarizing radiological findings of exostoses situated at the plantar part of the calcaneus or at the insertion point of the plantar aponeurosis. Various authors give values for the incidence of 8-88 % in an unselected population [2‐4]. Described risk factors are old age, obesity and foot or leg deformities. Further data concerning histology, symptoms and alternative therapy methods are given elsewhere [5, 6].

Our first randomized trial on plantar fasciitis [5] comparing the analgesic effect of a standard dose (1.0Gy two times a week up to a total dose of 6Gy) to that of a very low dose (0.1Gy two times a week up to a total dose of 0.6Gy) resulted in a highly significant superiority of the standard dose. Thus, to our opinion the analgesic effect of low-dose radiotherapy for painful heel spur could be confirmed.

In the last 15 years, in-vitro data have shown that single doses in the range 0.5-0.7Gy might be even more effective than higher ones. Roedel et al. published in 2002 that single doses of 0.3-0,5 Gy lead to a local maximum of apoptosis in macrophages and a reduced E-selectin-presentation on endothelium cells combined with an enhanced expression of TGFß1 [7]. Hildebrand could also show in vitro that depending on modulation of cytokine-stimulated E-selectin-presentation leukocytes could less adhere to endothelium especially with single doses of 0.3-0.6 Gy. This finding also underlines the anti-inflammatory effect of low-dose therapy [8]. Additionally, Gaipl et al. (2009) revealed a maximum of activity-induced cell death in polymorphnuclear cells by the use of single doses of 0.3 Gy in radiotherapy [9]. Further anti-inflammatory effects of low-dose radiotherapy seem to be a reduced CCL-20-chemokine-expression, a reduced adhesion of granulocytes to endothelium cells and an enhanced activity of AP-1 DNA ligation strength [10]. An actual review article stresses the increased expression of the X-linked inhibitor of apoptosis and TGFß1 and the reduced expression of E- and L-selectin, Interleukin-1 and CCL20 through macrophages and polymorphnuclear cells using single doses between 0.5 and 0.7 Gy [11]. Another review article shows additionally high levels of hemioxigenase 1 (HO-1) and heat shock protein 70 (HSP 70) at a maximum using single doses of 0.5 Gy [12].

Thus, we conducted a second clinical prospective randomized multicenter trial in order to compare the analgesic effect of a (to that time) standard single dose of 1Gy to that of a lower dose of 0.5Gy keeping the total dose constant.

A total of 127 patients were included in this trial. A majority of 112 patients was treated in the University Hospital of Homburg, ten in the University Hospital of Regensburg, and the remaining five in the University Hospital of Mainz.

Nine patients had to be excluded after randomization either due to their refusal to undergo therapy or to radiotherapy with an incorrect dosage (that of the other arm). A further patient was excluded due to a critical lack of data. Finally, 59 patients were assigned to the standard dose group and the remaining 58 to the experimental dose group. Of those, 54 patients in the standard dose group and 53 in the experimental dose group could be followed-up for twelve weeks.

The aim of this multicenter randomized study was to compare the analgesic effect of standard single doses compared to lower ones keeping the total dose constant. At the time this trial was planned, the standard dose was 1.0Gy twice a week up to a total dose of 6Gy. Compared to this dosage we did not find any difference in our experimental arm (12 times 0.5Gy three times a week). In the meantime, a new standard of single doses or 0.5Gy twice a week up to a total dose of 3.0Gy has been established according to the results published by Heyd et al. [16] and Ott et al. [17]. Compared to this standard we did not see any benefit after escalation of the dose to 6Gy. In summary, we could not find any difference resulting in the assumption that the in-vivo results could not be translated into clinical pain relief.

The authors are well aware of the limitations of this trial. Because of the results of the interim analysis shown here without a reasonable probability to see a significant difference between the groups by recruiting further patients the study was closed prematurely which may limit its statistical power. A further reason for the early closure were the results published by Ott et al. [17] showing that the same grade and duration of pain relief can be achieved applying a total dose of 3 Gy in single fractions of 0.5 Gy twice a week compared to the known standard dose of 6 Gy in single fractions of 1.0 Gy twice a week at a high level of evidence. In the meantime, the standard total dosage has been lowered to 3 Gy in many institutions in Germany according to the ALARA principle (keep the dose as low as reasonably achievable). Thus, continuation of the trial could have lead to an ethical problem.

Furthermore, the trial was conducted in a randomized manner but not blinded to the patient or the physician. Using a linear accelerator, it seemed nearly impossible and unethical to perform a blinded radiotherapy. Finally, the results may have been confounded by the fact that concomitant therapy with oral analgesics was not limited. Otherwise, it may be assumed that limitation of concomitant medication would have caused an unwanted selection bias.

Numerous retrospective trials have shown that low-dose radiotherapy for painful heel spur has a good analgesic effect, pain relief has been noticed in 65 – 90 % of the patients (literature table in [18]). However, a certain placebo effect is still under discussion [19]. Goldie et al. examined this effect in 399 patients. They found a response in 60 % of the patients whether irradiated or not; these results made the effect of radiotherapy questionable [20]. The trial, however, has been criticized because of missing clearly defined endpoints: furthermore the therapy was started in an acute stage of the diseases and the authors did not wait for spontaneous pain remissions. In the meantime, several more modern trials have shown the analgesic effect of radiotherapy. Seegenschmiedt et al. [3] performed a randomized trial treating 141 patients (170 heels) for painful heel spur using orthovoltage, comparing three radiotherapy schedules: 1 Gy/fraction up to 12 Gy, 0.3 Gy/fraction up to 3 Gy and 0.5 Gy/fraction up to 5 Gy. The overall complete pain relief was reported in 67–72 % of the patients. The best results were seen after a total dose of 5 Gy. These results were confirmed by Schäfer et al. using a telecobalt machine, they achieved a complete pain relief in 58 % [33]. Heyd et al. used 6 MV photon beams of a linear accelerator, they noticed a frequency of pain relief of 69 % [4]. The same author group published a prospective randomized trial recently [16] comparing the effect of a total dose of 3 Gy (single fraction 0.5 Gy twice a week) to that of a total dose of 6 Gy (single fraction 1 Gy twice a week). Radiotherapy was reported very efficient, however a dependency on dose could not be noticed. Mücke et al. looked for prognostic factors for pain relief in a multicenter trial [18]. They found an overall response in 60.9 %. Significant favourable prognostic factors for pain relief were a patient's age over 58 years, the use of megavoltage techniques and the number of therapy series required. Niewald et al. showed in a recent prospective study that a total dose of 6 Gy with single doses of 1 Gy twice a week is much more effective than a total dose of 0.6 Gy with single doses of 0.1 Gy twice a week concerning analgesic effect and showed that a total doses of 6 Gy makes this effect durable for at least 1 year [5]. The important results published by Ott et al. [17] have been mentioned earlier.

Radiation therapy yields important pain relief in patients with painful heel spur (plantar fasciitis). The very encouraging laboratory results showing an enhanced effect of single doses in the range of 0.5-0.7 Gy compared to higher ones could not be translated into clinical practice. Until now we found no plausible explanation for this result. Further trials based on a total dose of 3 Gy will be necessary to explore the best dose schedule. This trial will be continued until all patients have reached a follow-up duration of 48 weeks. Only these long-term results will allow a final decision.